title: Identification of tubulin drug binding sites and prediction of relative differences in binding affinities to tubulin isotypes using digital signal processing.
abstract: Microtubules are involved in numerous cellular processes including chromosome segregation during mitosis and, as a result, their constituent protein, tubulin, has become a successful target of several chemotherapeutic drugs. In general, these drugs bind indiscriminately to tubulin within both cancerous and healthy cells, resulting in unwanted side effects. However, differences between beta-tubulin isotypes expressed in a wide range of cell types may aid in the development of anti-tubulin drugs having increased specificity for only certain types of cells. Here, we describe a digital signal processing (DSP) method that is capable of predicting hot spots for the tubulin family of proteins as well as determining relative differences in binding affinities to these hot spots based only on the primary sequence of 10 human tubulin isotypes. Due to the fact that several drug binding sites have already been characterized within beta-tubulin, we are able to correlate hot spots with the binding sites for known chemotherapy drugs. We have also verified the accuracy of this method using the correlation between the binding affinities of characterized drugs and the tubulin isotypes. Additionally, the DSP method enables the rapid estimation of relative differences in binding affinities within the binding sites of tubulin isotypes that are yet to be experimentally determined.
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, ECEFR, 9701 116 Street, Edmonton, AB, Canada T6G2V4.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: J Torin
authors.initials: JT
authors.lastname: Huzil
authors.forename: Holly
authors.initials: H
authors.lastname: Freedman
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramachandran
authors.forename: Andreas
authors.initials: A
authors.lastname: Antoniou
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kurgan
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D020033:Protein Isoforms; D014404:Tubulin